Skeletal muscle is a highly adaptable tissue that responds to a variety of signals to modify its size and functional capacity. Loss of skeletal muscle mass and function occurs to varying degrees in all individuals with age and is a major contributor to increased frailty, loss of mobiliy, and increased mortality. During the aging process, skeletal muscle also develops a resistance to grow (or hypertrophy) in response to growth stimuli such as increased loading and nutrition. An inability to respond to increased loading and nutritional intake to restore muscle size following extended periods of bed rest or inactivity could accelerate the progression of age-associated muscle loss, and contribute to the loss of functional mobility, independence and the onset of frailty often observed in the elderly. While many studies have investigated the effects of aging on the ability of otherwise healthy muscle to grow in response to resistance exercise, few have studied the effects of aging on load-induced growth following a period of muscle wasting as occurs following immobilization and bed rest. Since periods of enforced bed rest become more common with age, the impaired recovery of muscle mass and function is a significant clinical concern that can affect the long-term health and well-being of patients. Consequently, the specific objective of this proposal is to understand the cellular and molecular mechanisms underlying the resistance of muscle to grow in response to increased loading and nutrition following disuse-induced atrophy. Our working hypothesis is that the age-associated loss of load-induced muscle growth is the result of increased metabolic stress resulting in the activation of protein degradation and a concomitant inhibition of translation initiation and ribosome biogenesis resulting in negative protein balance. In this proposal we will utilize a rodent model that we have shown to closely replicate the human condition, i.e., hindlimb reloading following tail suspension unloading, to study the effect of age on both skeletal muscle atrophy and the recovery of muscle mass following atrophy. The effects of unloading/reloading on skeletal muscle mass and contractile function will be studied in young (9 month old) and old (28 month old) Fisher 344-Brown Norway rats, a well-established rodent aging model. The specific aims for this proposal are to: (1) Determine whether decreased activity and increased metabolic stress underlie the reduced muscle growth observed following reloading in aged rats. (2) Determine whether protein degradation pathways (ubiquitin proteasome system, calpain, lysosomal proteases) are activated to a greater extent in aged rats following reloading. (3) Determine whether protein synthesis is decreased in aged rats following increased loading due to impaired amino acid uptake and inhibition of translation initiation through mTORC1 (mammalian target of rapamycin). Where possible, specific nutritional (protein supplementation) and pharmaceutical (SIRT1 activation) interventions to reverse the effects of aging will be tested in our animal model before translation into a clinical population. The studies outlined in this proposal will provide fundamental knowledge about the cellular mechanism regulating muscle growth following atrophy as a function of age, as well as identify potential treatments for translation into humans. This research is of particular relevance to the Veteran's Administration since the population of older veterans in the system is rising, and the effects of skeletal muscle atrophy are more debilitating and costly in the elderly. The long-term goal of the research outlined in this proposa is the development of effective therapies for the enhancement of muscle recovery following atrophy in the elderly, which represents a significant problem and unmet clinical need. PUBLIC HEALTH RELEVANCE: To date there are no effective therapeutic treatments for preventing age-related loss of muscle mass and function, or to enhance recovery of muscle following atrophy and injury. The studies outlined in this proposal will provide fundamental knowledge about the cellular and molecular mechanisms regulating muscle growth following atrophy as a function of age, as well as identify potential treatments for translation into humans. This research is of particular relevance to the Veteran's Administration since a significant number of patients in the system will require rehabilitation to recover skeletal muscle mass following atrophy induced by bed rest, immobilization, or neural trauma. The aging population represents a growing medical and monetary concern for the VA, since the elderly will suffer greater consequences of atrophy due to poor recovery. The development of effective therapies for the enhancement of muscle recovery following atrophy in the elderly is an unmet clinical need, and is the long-term goal of the research outlined in this proposal.